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Hepatitis B virus X protein induces expression of alpha-fetoprotein and activates PI3K/mTOR signaling pathway in liver cells.

Zhu M, Guo J, Li W, Lu Y, Fu S, Xie X, Xia H, Dong X, Chen Y, Quan M, Zheng S, Xie K, Li M - Oncotarget (2015)

Bottom Line: We found that HBV induced the expression of AFP before that of oncogenes, e.g., Src, Ras and chemokine (C-X-C motif) receptor 4 (CXCR4), and AFP activated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in HBV-related HCC tissues and in human liver cells transfected with HBx.Cytoplasmic AFP interacted with and inhibited phosphatase and tensin homolog deleted on chromosome 10 (PTEN), activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and promoting mTOR-mediated stimulation of the transcription factor hypoxia inducible factor-1α (HIF-1α), and therefore led to the activation of the promoters of Src, CXCR4, and Ras genes.On the contrary, reduced expression of AFP by siRNA resulted in the repression of p-mTOR, pAKT, Src, CXCR4, and Ras in human malignant liver cells.

View Article: PubMed Central - PubMed

Affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.

ABSTRACT
The hepatitis B virus (HBV)-X protein (HBx) induces malignant transformation of liver cells, and elevated expression of alpha-fetoprotein (AFP) is a significant biomarker of hepatocarcinogenesis. However, the role of AFP in HBV-related hepatocarcinogenesis is unclear. In this study, we investigated the regulatory impact of AFP expression on HBx-mediated malignant transformation of human hepatocytes. We found that HBV induced the expression of AFP before that of oncogenes, e.g., Src, Ras and chemokine (C-X-C motif) receptor 4 (CXCR4), and AFP activated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in HBV-related HCC tissues and in human liver cells transfected with HBx. Cytoplasmic AFP interacted with and inhibited phosphatase and tensin homolog deleted on chromosome 10 (PTEN), activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and promoting mTOR-mediated stimulation of the transcription factor hypoxia inducible factor-1α (HIF-1α), and therefore led to the activation of the promoters of Src, CXCR4, and Ras genes. On the contrary, reduced expression of AFP by siRNA resulted in the repression of p-mTOR, pAKT, Src, CXCR4, and Ras in human malignant liver cells. Taken together, for the first time our study indicates that HBx-induced AFP expression critically promote malignant transformation in liver cells through the activation of PI3K/mTOR signaling.

No MeSH data available.


Related in: MedlinePlus

Effects of pcDNA3.1-HBx on the expression of AFP, Src, CXCR4, Ras, pAKT(Ser473), and p-mTOR(Ser2448) in liver cells(A) L-02 and CHL liver cells were transfected with pcDNA3.1-HBx and expression of HBx was measured 48 hours later by Western blotting. (B) Expression of Src, CXCR4, Ras, pAKT(Ser473), and p-mTOR(Ser2448) was measured by Western blotting 1, 7, 14, 21, and 28 days after transfection. Results are from one representative experiment of three.
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Figure 2: Effects of pcDNA3.1-HBx on the expression of AFP, Src, CXCR4, Ras, pAKT(Ser473), and p-mTOR(Ser2448) in liver cells(A) L-02 and CHL liver cells were transfected with pcDNA3.1-HBx and expression of HBx was measured 48 hours later by Western blotting. (B) Expression of Src, CXCR4, Ras, pAKT(Ser473), and p-mTOR(Ser2448) was measured by Western blotting 1, 7, 14, 21, and 28 days after transfection. Results are from one representative experiment of three.

Mentions: We transfected a vector expressing the HBV protein HBx, pcDNA3.1-HBx, into human liver cell lines L-02 and CHL and measured the impact of pcDNA3.1-HBx on the expression of AFP and the oncogenes Src, CXCR4, and Ras. The pcDNA3.1-HBx-mediated induction of HBx expression in L-02 and CHL cells was evident 2 days after transfection and remained elevated between 7 and 28 days after transfection (Figure 2A). Expression of AFP was emerged after transfected with pcDNA3.1-HBx for 7 days and persisted increasing after 28 days. Expression of CXCR4 and Ras was enhanced 7 day after transfection and increased for 28 days in both L-02 and CHL cells (Figure 2B). The expressions of AFP and CXCR4 were further confirmed at the mRNA levels by quantitative RT-PCR analysis (Supplementary Figure 1B). Src expression was elevated 14 days after transfection in both L-02 and CHL cells (Figure 2B).


Hepatitis B virus X protein induces expression of alpha-fetoprotein and activates PI3K/mTOR signaling pathway in liver cells.

Zhu M, Guo J, Li W, Lu Y, Fu S, Xie X, Xia H, Dong X, Chen Y, Quan M, Zheng S, Xie K, Li M - Oncotarget (2015)

Effects of pcDNA3.1-HBx on the expression of AFP, Src, CXCR4, Ras, pAKT(Ser473), and p-mTOR(Ser2448) in liver cells(A) L-02 and CHL liver cells were transfected with pcDNA3.1-HBx and expression of HBx was measured 48 hours later by Western blotting. (B) Expression of Src, CXCR4, Ras, pAKT(Ser473), and p-mTOR(Ser2448) was measured by Western blotting 1, 7, 14, 21, and 28 days after transfection. Results are from one representative experiment of three.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494932&req=5

Figure 2: Effects of pcDNA3.1-HBx on the expression of AFP, Src, CXCR4, Ras, pAKT(Ser473), and p-mTOR(Ser2448) in liver cells(A) L-02 and CHL liver cells were transfected with pcDNA3.1-HBx and expression of HBx was measured 48 hours later by Western blotting. (B) Expression of Src, CXCR4, Ras, pAKT(Ser473), and p-mTOR(Ser2448) was measured by Western blotting 1, 7, 14, 21, and 28 days after transfection. Results are from one representative experiment of three.
Mentions: We transfected a vector expressing the HBV protein HBx, pcDNA3.1-HBx, into human liver cell lines L-02 and CHL and measured the impact of pcDNA3.1-HBx on the expression of AFP and the oncogenes Src, CXCR4, and Ras. The pcDNA3.1-HBx-mediated induction of HBx expression in L-02 and CHL cells was evident 2 days after transfection and remained elevated between 7 and 28 days after transfection (Figure 2A). Expression of AFP was emerged after transfected with pcDNA3.1-HBx for 7 days and persisted increasing after 28 days. Expression of CXCR4 and Ras was enhanced 7 day after transfection and increased for 28 days in both L-02 and CHL cells (Figure 2B). The expressions of AFP and CXCR4 were further confirmed at the mRNA levels by quantitative RT-PCR analysis (Supplementary Figure 1B). Src expression was elevated 14 days after transfection in both L-02 and CHL cells (Figure 2B).

Bottom Line: We found that HBV induced the expression of AFP before that of oncogenes, e.g., Src, Ras and chemokine (C-X-C motif) receptor 4 (CXCR4), and AFP activated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in HBV-related HCC tissues and in human liver cells transfected with HBx.Cytoplasmic AFP interacted with and inhibited phosphatase and tensin homolog deleted on chromosome 10 (PTEN), activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and promoting mTOR-mediated stimulation of the transcription factor hypoxia inducible factor-1α (HIF-1α), and therefore led to the activation of the promoters of Src, CXCR4, and Ras genes.On the contrary, reduced expression of AFP by siRNA resulted in the repression of p-mTOR, pAKT, Src, CXCR4, and Ras in human malignant liver cells.

View Article: PubMed Central - PubMed

Affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.

ABSTRACT
The hepatitis B virus (HBV)-X protein (HBx) induces malignant transformation of liver cells, and elevated expression of alpha-fetoprotein (AFP) is a significant biomarker of hepatocarcinogenesis. However, the role of AFP in HBV-related hepatocarcinogenesis is unclear. In this study, we investigated the regulatory impact of AFP expression on HBx-mediated malignant transformation of human hepatocytes. We found that HBV induced the expression of AFP before that of oncogenes, e.g., Src, Ras and chemokine (C-X-C motif) receptor 4 (CXCR4), and AFP activated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in HBV-related HCC tissues and in human liver cells transfected with HBx. Cytoplasmic AFP interacted with and inhibited phosphatase and tensin homolog deleted on chromosome 10 (PTEN), activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and promoting mTOR-mediated stimulation of the transcription factor hypoxia inducible factor-1α (HIF-1α), and therefore led to the activation of the promoters of Src, CXCR4, and Ras genes. On the contrary, reduced expression of AFP by siRNA resulted in the repression of p-mTOR, pAKT, Src, CXCR4, and Ras in human malignant liver cells. Taken together, for the first time our study indicates that HBx-induced AFP expression critically promote malignant transformation in liver cells through the activation of PI3K/mTOR signaling.

No MeSH data available.


Related in: MedlinePlus